Cross-sections of vascular walls show an asymmetrical structure, which consists of tunica intima consisting of endothelium; connective tissues consisting of elastin, collagen fibers, etc.; tunica media consisting of smooth muscles; and tunica adventitia consisting of collagen fiber layer. The asymmetrical structure of blood vessels is known to inhibit thrombosis, prevent vascular leakage, and provide fluidity of blood vessels. Specifically, in “tunica intima” consisting of vascular endothelium, polymers of sugar components are accumulated on the surface and form a glycocalyx layer, which has the roles of directly controlling the blood flow and preventing the direct contact between blood and epithelial cells, thereby inhibiting the entrance of blood components into epithelial cells. In addition, the glycocalyx layer is known to be involved in various physiological activities such as the regulation of blood vessel tone, exchange of fluids and solutes between blood and tissue, leukocyte migration, hemostasis and blood coagulation, inflammatory responses, etc.
It is known that once the glycocalyx layer is damaged, it firstly results in the loss of vascular function, and secondly, physiologically activities related to blood vessels are inhibited. The most serious effect caused by the damage in the glycocalyx layer is the functional loss of blood vessels, and once the glycocalyx layer is damaged by mechanical stimulation such as wounds, surgeries, etc., the components in the blood may escape through the epithelial cells to the outside of the blood vessels. Such a symptom where the components in the blood flow out of the blood vessels is called vascular leakage. The blood leakage may be induced by excess oxygen radicals, in addition to the mechanical stimulation described above, and may also be induced by various diseases such as ulcer of gastric organs, internal bleeding, inflammation, ischemia, diabetes, etc.
The representative example of the diseases which induce blood leakage may be vascular leak syndrome. The vascular leak syndrome is a disease where blood plasma is leaked through the vascular wall by extravasation and thereby induces edema of neighboring tissues. In general, vascular leak syndrome is known to occur as a side-effect of treatments using interleukin-2. However, since vascular leak syndrome is known to not occur in all of the patients who received the treatment using interleukin-2, a possibility was raised that the syndrome may occur due to genetic reasons of individual patients, and thus vascular leak syndrome is also considered as a kind of a genetic disease. However, since it is not easy to obtain samples of patients induced with vascular leak syndrome, there was a problem in that it was not easy to study vascular leakage symptoms via vascular leak syndrome. As such, as an alternative to patients with vascular leak syndrome, various studies were performed in diabetic patients with frequent vascular leakage. As a result, it was found that vascular leakage is induced by overexpression of vascular endothelial growth factor (VEGF). That is, it was reported that the VEGF overexpression induced at the onset of diabetes can decompose VE-cadherin, which has an important role of maintaining the binding between epithelial cells, and decreases the binding between epithelial cells and induces the damage of glycocalyx layer, thereby causing the occurrence of vascular leakage. Additionally, the vascular leakage may be induced by a surgical process for the treatment of cardiovascular disease. For example, as a method for treating an aneurysm, which is a disease where part of an artery expands when the artery wall weakens or the inner pressure of the artery increases, a surgical method of inserting an prosthesis such as a stent between blood vessels where an aneurysm occurred is being used for preventing a further influx of a blood flow into the expanded area, and vascular leakage may occur in the neighboring region of the stent. Such vascular leakage occurring during the treatment of an aneurysm is also called “endoleak”, and when endoleak occurs, there is a problem in that a second surgery is needed. Such vascular leakage basically causes the loss of blood, lowers blood pressure, etc., and as a result, a secondary damage due to anemia or ischemia may be induced. Accordingly, active studies have been focused on the development of a method for effective treatment of vascular leakage.
For example, International Patent Publication No. WO 2010/081172 discloses compounds that prevent vascular leakage; Korean Patent No. 958578 discloses a stent that can prevent vascular leakage during the treatment of aneurysm; Korean Patent No. 1239495 discloses a method for treating diabetic retinopathy using recombinant adenovirus which expresses αA-crystallin gene; and International Patent Publication No. WO 2014/025127 discloses a C-peptide which can suppress vascular leakage by inhibiting the VEGF-induced VE-cadherin degradation. However, among the developed technologies above, the use of the stent can be limited to the treatment of arteries only, and there is a possibility that compounds or C-peptide can cause a side effect. Therefore, there is a need for the development of a formulation for safer and more effective treatment of vascular leakage.